CSL / JIFSAN Symposium
on Food Safety and Nutrition
Food Safety and “Nutritional Risk”:
“Bioactive” Food Components
Alan M. Rulis
FDA / CFSAN
June 29, 2005
Olestra as a ““case
case study
”
study”
on ““bioactive”
bioactive” ingredients ??
This presentation focuses a good deal on FDA
’s safety review of the food
FDA’s
additive petition for the fat substitute ““olestra.”
olestra.”
Olestra is decidedly NOT ““bioactive”
bioactive” in the chemical sense. Yet, its safety
review signals landmark issues for the
als that
the evaluation
evaluation of
of many
many materi
materials
are the focus of this symposium,
he
symposium, i.e.,
i.e., when we must expand beyond tthe
realm of traditional toxicological endpoints into nutrition, gas
trointestinal
gastrointestinal
physiology, human tolerance data, etc., and also expand our reli
ance on
reliance
clinical data, and
’s
and active
active and
and passive
passive post
post market
market surveillance.
surveillance. The
The FDA
FDA’s
review of olestra brought many of these issues into sharp focus for the
first time.
These facets of safety review are now commonly included in the
evaluation of at least some, if not all, bioactive food ingredie
nts, and are
ingredients,
”
major attributes of the developing field of ““nutritional
nutritional safety
safety assessment.
assessment.”
This presentation will:
ƒ Outline scientific principles and legal
standard for safety assessment of food
components; focus on the case of “olestra”
…leading to…
ƒ Approaches for regulating food novel
components, including, ultimately,
“bioactive” ones...and, thereby leading to…
ƒ …outlining aspects of the emerging field of
“Nutritional Safety Assessment”
Food Safety Decision Framework
in U.S. Law
U.S. law approaches different segments or
components of the food supply differently;
e.g., food itself, “generally recognized as
safe” food ingredients, food additives, color
additives, food contact substances,
pesticide residues, animal drugs,
environmental contaminants of food, “prior
sanctioned” food ingredients, dietary
supplements, infant formula, etc.
A Core Statute for Food Ingredient
Safety: Sec. 409 of the FD&C Act
ƒ Defines “food additive” (w/ GRAS exemption)
ƒ Requires premarket approval of new uses of
food additives, if not “GRAS”
ƒ Establishes the standard of data review
ƒ Establishes the standard of safety
ƒ Establishes formal rulemaking procedures for
petition review
ƒ ------------since FDAMA of 1997:-----------------ƒ Defines “food contact substance” (FCS)
ƒ Establishes a premarket notification program
for food contact substances
Standard of Review
“Fair evaluation of the data . . .”
House of Representatives, Report No. 2284, ““Food
Food
Additives Amendment of 1958
”
1958”
Committee on Interstate & Foreign Commerce, 85th
Congress, 2nd Session, July 28, 1958
“The committee feels that the Secretary’s
findings of fact and orders should not be based
on isolated evidence in the record, which
evidence in and of itself may be considered
substantial without taking account of the
contradictory evidence of equal or even greater
substance . . . .”
Safety Standard
“Reasonable certainty of no harm . . .”
REASONABLE CERTAINTY OF NO HARM
Legislative History of the FD&C Act
The concept of safety used in this legislation
involves the question of whether a substance is
hazardous to the health of man or animal.
Safety requires proof of a reasonable certainty
that no harm will result from the proposed use
of an additive.
It does not -- and cannot -- require proof
beyond any possible doubt that no harm will
result under any conceivable circumstance.
H.R. Report No. 2284, 85th Congress 1958
The RCNH Standard of Safety
for Food Additives
The petitioner has the burden to
demonstrate a “reasonable certainty of
no harm” from the intended use of the
additive
This requires that the FDA assess whether
it has received from the petitioner
adequately documented answers to
appropriate questions of probative value.
Reasonable Certainty of
No Harm
What does
“Reasonable Certainty of No Harm”
mean?
Reasonable Certainty of
No Harm
It is not intended to ensure, nor is it
possible to ensure, safety with
absolute certainty:
i.e., “Reasonable Certainty of No
Harm” is not “Certainty of No
Theoretical Possibility of Harm.”
Traditional Safety Evaluation
(Petitions)
ƒ A “full blown,” exhaustive safety evaluation
of all appropriate data, information and
studies, with agency “ownership” of the
ultimate safety decision and publication of
its decision and supporting rationale in the
Federal Register.
Toxicological Testing
The CFSAN ““Redbook”
Redbook”
Minimum Toxicity Tests
Short-term tests for genetic toxicity
Concern Levels
I
II
III
X
X
X
X
X
Subchronic tox tests with rodents
X
X
Subchronic tox tests with nonrodents
X
Reproduction study w/ teratology
phase
X
Metabolism & pharmacokinetic
studies
Short-term tox tests with rodents
X
X
One-Yr tox tests with non-rodents
X
Carcinogenicity study with rodents
X
Chronic tox/ carcinogenicity study
with rodents
X
The ““Toxicological”
Toxicological” Safety Assessment Model
(Based on the Review of Toxicological Data)
„
„
Requires defining population exposure
to the additive, “Estimated Daily
Intake” (or EDI), and
Comparing that to an “Acceptable
Daily Intake” (ADI) from toxicological
studies
The ““Toxicological”
Toxicological” Safety Assessment Model
(Based on the Review of Toxicological Data)
ƒ
ƒ
ƒ
ƒ
Lifetime-average, “high eaters only” EDI
HNEL from lifetime animal studies
Threshold behavior for toxic effects
Application of appropriate safety
(uncertainty) factors (e.g., 10x and 10x)
ƒ Acceptable Daily Intake or ADI
ƒ Comparison of the EDI to the ADI
ƒ No effects at estimated consumption levels
The ““Circle”
Circle” of
Reasonable Certainty of No Harm
As a metaphor for the process,
think of the goal as: “being within a circle of unit radius”
as defined below:
“Safe” within the meaning
of the FD&C Act
EDI/ADI
Beyond the Traditional
Toxicology Framework
The Case of the Food Additive
OLESTRA
““Olestra”
Olestra”
a macronutrient substitute for fat
„
„
„
„
Under the FD&C Act, olestra was a new food
additive use…
1987 Petition from P&G for olestra use as a fat
substitute (later only for use in “savory snacks”)
…requiring FDA premarket safety evaluation.
This, in turn, required the review of data on likely
human exposure, toxicological properties and, as it
turns out, effects on human physiology and
nutrition, as well.
Olestra
…What is it?
Olestra…What
„
„
Olestra is a Sucrose Polyester, a mixture
of substances formed by chemical
combination of sucrose with 6, 7, or 8 fatty
acids.
It has many of the physical properties of
natural fats, and therefore can
technologically substitute for fat in food
manufacture.
Olestra: Molecular Structure
6,7 or 8
C12
-C 20 fatty acids
12-C20
esterified
esterified to
to the
the two
two
sucrose rings
Beyond ““Toxicity”
Toxicity” Studies
„
„
For some food ingredients / additives, including
olestra, the traditional portfolio of “toxicity” studies
is of limited value in defining the entire safety
picture because it does not produce a
comprehensive view of additive safety under
conditions of use.
When that is the case, then other information
must be sought and evaluated:
Beyond ““Toxicity”
Toxicity” Studies
ƒ For olestra there was not an “ADI,” as such…
But…
ƒ There was the likelihood of be significant
“nutritional effects”
ƒ As well as significant “physiological effects”
Beyond ““Toxicity”
Toxicity” Studies
In fact….
ƒ Clinical data may become as important as
“toxicological” data
ƒ Chemical Identity / SAR may be of value
ƒ “ADME” studies may be more important
ƒ Human “Tolerance” studies can play a role
ƒ Clinical studies of various types may be needed
ƒ Post-market monitoring (both passive and
active surveillance) may be justified as well
Summary of Olestra Data Review
„
So, let’s review olestra’s overall data picture:
z
z
z
z
z
Chemical identity and probable consumption
A portfolio of “traditional” toxicity studies in a
range of species
Nutritional Impact Studies (swine and humans)
GI effects, physiological responses from clinical
studies
FDA’s Decision Process
Summary of Olestra Data Review
„
Identity and Use
z
z
z
z
z
Manufacturing Process
Constituents
Specifications
Stability
Estimated Daily Intake; “probable consumption”
Summary of Olestra Data Review
Toxicity Testing Data
„
Toxicity Data
z
z
z
z
ADME (rat, guinea pig, mini-pig)
Teratology studies
Sub-Chronic Feeding Studies (rats, 90 d)
Chronic / Carcinogenicity Feeding Studies in rats and
mice; dog feeding studies
No adverse effects seen upon which to determine
an ADI in the traditional sense.
Summary of Olestra Data Review
Drug Interference Data
„
Effect of Olestra on Absorption of Drugs (?)
z
z
z
z
Selected Lipophilic Drugs
Range of lipophilicity from aspirin to ethinyl
estradiol
Effect of olestra on drug bioavailability
Effect on systemic levels of steroidal
hormones in women taking oral contraceptives
Summary of Olestra Data Review
Nutritional Studies
„
Nutritional Studies (in both animals / humans)
z
z
z
z
z
Hypothesis; olestra interferes with the absorption
of fat-soluble nutrients when those nutrients
partition into olestra in the GI tract.
Both fat-soluble and water soluble nutrients
studied
Folate, Vitamin B12, calcium, zinc, and iron
Vitamins A, D, E, K
Studies (DR, VR) conducted in both humans and
pigs
Studies to Assess Nutritional Effects
of Olestra Consumption
Human Studies
„
„
„
„
„
8-Wk clinical DR
8-Wk clinical VR
6-Wk V D/K status
16-Wk V E status
14-d V A/fat absorption
Pig Studies
„
„
„
„
„
26-Wk DR & VR
39-Wk VR
12-Wk DR
12-Wk VR
4-Wk “dietary context”
Summary of Olestra Data Review
Human Clinical Studies
„
Primary reliance on two 8-week clinical
studies on dose-response and vitamin
restoration:
z
z
z
z
z
Complete control of nutrient intake
Double-blind placebo-controlled
Olestra added to food vs. triglyceride; 0, 8, 20,
32 g/d
Diets 15% cal from protein; 55% from carbs;
and still 30% from triglycerides
GI symptoms recorded if experienced
Summary of Olestra Data Review
88-Wk
-Wk Clinical Dose
-Response Study
Dose-Response
„
„
Serum levels of A,D,E,K, folate, B12, and
Zinc measured
Decreases in serum levels of fat sol.
Vitamins seen (serum retinol only for A)
Summary of Olestra Data Review
88-Wk
-Wk Clin. Vitamin Restoration Study
„
Determined levels of vitamins A,D,E, and
K to add back to food to compensate for
any losses due to olestra
Summary of Olestra Data Review
Studies in Swine
„
„
Five nutritional studies of varying lengths
(12, 12, 26, 39, and 4 Wks).
Helped determine DR; and Vitamin
restoration levels appropriate to avoid any
lowering of serum levels (or liver stores of
Vitamin A)
Nutrient Status Measurements
in 12
-Week Pig DR Study
12-Week
Nutrient
Vitamin A……….
Vitamin E……….
Vitamin D……….
Vitamin K……….
Folate……………
Vitamin B12…….
Calcium…………
Phosphorous….
Iron………………
Zinc………………
Measurements
Liver & Serum conc.
Liver, Serum, Adipose tissue conc.
Serum Conc of different forms
Prothrombin time
Plasma concentration
Liver concentration
Bone, serum Ca, bone ash conc.
Bone and serum concentration
Liver iron and serum concs.
Liver, bone, serum concentrations
Carotenoids
„
„
„
Serum levels are affected
Much discussion from all sides (the petitioner,
many comments, special FDA consultants, food
advisory committee, NCI, and NEI experts)
FDA concluded that effects of olestra on
absorption of lipophilic carotenoids, “reasonably
certain to be insignificant from a public health
standpoint.”
GI Effects
Issues that were of potential concern to FDA:
1. Potential for loose stools or diarrhea to result
in electrolyte and fluid loss
2. Interference with normal daily life
3. Special concerns for subpopulations
(children, GI compromised, the elderly)
4. Microfloral changes in the gut
GI Effects
„
After review by FDA of submitted studies,
and the FDA Food Advisory Committee,
including gastroenterologists, etc., FDA
concluded:
z
z
Reasonable certainty of no harm w.r.t.
potential for olestra to cause GI effects
Could cause loose stools, but not adverse
because do not threaten health.
Some Conclusions from the
Olestra Data Review
„
Conclusions from Nutritional Studies:
z
z
z
„
Olestra affects the status of fat sol. vitamins
Potential losses can be compensated for
Compensation levels determined
quantitatively
Conclusions on GI Effects:
z
There are effects, but they do not adversely
affect health
FDA
’s Safety Review: Summary
FDA’s
„
„
„
Standard regimen of toxicological studies
Supplemented by a range of special studies
(nutritional impact studies, e.g., in swine and
other species, including human clinical studies) to
elicit information about the nutritional
characteristics and impact of the material on those
who ingest it.
Consultations 1/1 with and a roster of noted
experts on animal and human nutrition,
physiology, medicine, etc., B. Schneeman, then of
U. Cal. Davis, as primary consultant.
FDA
’s Safety Review: Summary
FDA’s
„
„
„
„
„
„
„
Separate consults w/ NCI (Dr. Greenwald) re:
carotenoids, and NEI (Dr. Kupfer) re: no macular
degeneration potential
Assembling of FDA’s Food Advisory Committee
(4 days in November 1995)
Special Labeling required (to preclude product
misbranding in the marketplace; interim
requirement)
Use of passive and active post market surveillance
Final regulation published FR January 30, 1996
Second FAC June 1998
Labeling requirement rescinded, FR August 2003
Labeling of Foods
Containing Olestra
„
Olestra-containing foods were originally
required to carry the following label
statement:
This Product Contains Olestra. Olestra may
cause abdominal cramping and loose stools. Olestra
inhibits the absorption of some vitamins and other
nutrients. Vitamins A, D, E, and K have been added.
Overall FDA Conclusions
„
„
„
„
„
„
„
„
„
Olestra is not toxic, carcinogenic, genotoxic, or teratogenic.
It is essentially not absorbed or metabolized.
It has an effect on the absorption of vitamins A, D, E, and K.
It is possible to supplement foods containing olestra with all four
vitamins so as to compensate for amounts not absorbed from the diet
due to the action of olestra.
No harmful effects on water soluble vitamins / minerals, including
vitamin D mediated calcium uptake.
Carotenoids need not be compensated for.
GI effects seen do not represent significant adverse health
consequences.
FDA did initially require a label statement, active and passive
postmarket monitoring, and a follow-up Food Advisory Committee
within 30 months of approval.
Other, later studies (home use study; n=3000) show little problem
A More Complex ““Circle”
Circle” of
Reasonable Certainty of No Harm
Nutritional Effects
(Nutrient Depletion
and Restoration)
Human
Tolerance
Our
Our metaphorical
metaphorical circle
circle of
of RCNH
RCNH
has
has become
become more
more complicated!
complicated!
Identity & Exposure
(Dose Response)
(physiological
effects; GI)
EDI/ADI
?
Drug Interference
Effects
Postmarket
Monitoring
Requirements
Beyond the ““Tox”
Tox” Framework:
(other areas where ADI concept alone may not be feasible)
ƒ Macro Ingredient Substitutes
• lipids
• carbohydrates
• proteins
ƒ Enzymes used in food processing
ƒ Fiber sources
ƒ Complex mixtures
ƒ Irradiated food
ƒ Herbals and other “bioactive” ingredients in
conventional foods and supplements
““Generally
Generally Recognized as Safe
”
Safe”
(GRAS)
Food Ingredients
FFDCA Definition of
““food
food additive
”
additive”
Th
e
“G
RA
S
Ex
em
pt
ion
”
“C
o
of mp
th on
e
de ent ”
fin pa
itio rt
n
201(s): “…any substance, the intended use of
which results or may be expected to result,
directly or indirectly, in its becoming a
component or otherwise affecting the
characteristics of any food…
if such substance is not generally recognized,
among experts qualified by scientific training
and experience…to be safe under the
conditions of its intended use”
GRAS Criteria: Comparing a GRAS
Substance to a Food Additive
Food Additive
FDA
“Technical
Element”
GRAS Substance
“Common
Common
Knowledge
Element”
Element
Generally
available
“Technical
Element”
Generally
accepted
GRAS Notification Procedure
based on the April 1997 FR Proposal
ƒ Voluntary
ƒ Notifier informs FDA of notifier’s view
that a use of a substance is GRAS
ƒ FDA responds by letter
3 Types of Response
to a GRAS Notice
ƒ FDA has “no questions”
ƒ Notice “does not provide a basis” for a
GRAS determination
ƒ At notifier’s request, FDA ceased to
evaluate the notice
ƒ Letters available on the Internet at
http://www.cfsan.fda.gov/~rdb/opa-gras.html
Other Examples of ““Bioactive”
Bioactive”
Food Ingredients?
„
„
„
„
Other macroingredient substitutes (for lipids,
carbohydrates, proteins)
Phytostanol Esters and Vegetable Oil Sterol
Esters in spreads (e.g., BenecolTM and Take
ControlTM)
Range of materials in GRAS Notices (enzymes,
fiber sources, herbs in conventional food)
Infant Formula Ingredients (e.g., novel sources of
DHA and ARA (LCPUFAs) as IF ingredients)
Other Examples of ““Bioactive”
Bioactive”
Food Ingredients in GRAS Notices
Examples where FDA Had “No Questions”:
TM)
• Vegetable oil sterol esters (Take ControlTM
TM)
• Phytostanol esters (BenecolTM
• Lactoferrin (GRN 77)
• Fructooligosaccharides (GRN 44)
• Small planktivorous pelagic body fish oil (GRN 102)
• Fish oil concentrate (GRN 105)
• Tuna oil (GRN 109)
• Diacylglycerol oil (GRNs 56 and 115)
• Inulin (GRN 118)
Other Examples of ““Bioactive”
Bioactive”
Food Ingredients in GRAS Notices
Examples where FDA “Questions” the
notifier’s GRAS notice:
• 6 Chinese Herbs (GRN 13)
• Garcinia cola (GRN 25)
• Crospovidone-cranberry extract (GRN 30)
• Hempseed oil (GRN 35)
• Milk thistle extract (GRN 66)
• Grape Seed Extract and Grape Skin Extract
(GRN 93)
Nutritional Risk Assessment?
„
For Nutrients added to food, or possibly
„
For other Bioactive ingredients in food
„
When we may expect nutrition related
effects aside from any potential
toxicological responses
Nutritional Risk Assessment
Requires:
• Expanded understanding of the exposure scenario of the
population and/or subgroups to substances of nutritional
interest or bioactive capacity in foods.
• The context of such exposure scenarios in comparison
to all other substances important to the diet.
• An understanding of the relevant dose/response
relationships, both beneficial and detrimental for
substances in the diet. (For nutrients or other bioactive
ingredients, this may include knowledge of both the
benefits of exposure to adequate levels, as well as risks
associated with ingesting too much, and the relevant
biochemical mechanisms of both.)
Nutritional Risk Assessment
„
z
z
z
An understanding of the inherent and methodological
errors and uncertainties associated with those doseresponse relationships.
Understanding of the interactions among nutrients or
other bioactive ingredients, and other components of the
diet that influence nutrient bioavailability or additive
safety
Impact of novel foods and food components on overall
dietary patterns
Physiological responses to the presence of the
substance in the diet, such as gastrointestinal
intolerance, etc.
Nutritional Risk Assessment
„
„
„
Data from animal models (both dose response and
mechanistic information) as well as human clinical data
Need for application of various types of quantitative and
statistical modeling techniques, including Monte Carlo
models for premarket and active and passive
postmarket monitoring and analyses
Other sources of relevant information on safety from the
new fields of genomics, metabolomics, proteomics, and
now, “nutrigenomics,” etc.
A Still More Complex ““Circle”
Circle” of
Reasonable Certainty of No Harm
Nutritional Effects
(Nutrient Depletion and
Restoration; gut microflora;
metabolism effects, etc. )
Identity & Exposure
(Dose Response; Similarity to
Food and normal bodily constituents)
Human
Tolerance
EDI/ADI
(?)
(physiological
effects; GI effects)
Allergenicity (FALCPA)
(FALCPA)
Drug Interference
Effects
Postmarket
Monitoring
Active/Passive
Active/Passive
Relative Food
-Related Concerns
Food-Related
(A Popular View)
ƒ Added Food Chemicals
ƒ Environmental Contaminants in Food
ƒ Food Hazards of Natural Origin
ƒ Microbial Contamination of Food
ƒ Nutritional Hazards
Relative Food
-Related Concerns
Food-Related
(A Possibly More Accurate View)
ƒ Nutritional Hazards
ƒ Microbial Contamination of Food
ƒ Food Hazards of Natural Origin
ƒ Environmental Contaminants in Food
ƒ Added Food Chemicals
Nutritional Safety Assessment
ties the top and bottom together!
ƒ Nutritional Hazards
ƒ Microbial Contamination of Food
ƒ Food Hazards of Natural Origin
ƒ Environmental Contaminants in
Food
ƒ Added Food Chemicals
The End!
Thank You!